tbuckley/cabot-search huggingface dataset:
Abstract 6587: Method to increase performance of genome-wide association study using imputation for Asian ancestry
Authors: GangPyo Ryu, Youngil Koh, Sung-soo Yoon
Journal: Cancer Research (2023)

Abstract The emergence of the large-scale public genomic database facilitates genome-wide association study. An unprecedented number of samples emerged, which enable elucidate valid genetic inferences and contribute to finding novel associations for various phenotypes including cancer. However, most of the genome data is from European-based ancestry, which leads to the disparity in study for relatively minor ethnic groups including Asian. Meanwhile, among public genomic database, TOPMed consortium consists of ~180k participants, over 60% of the 180k samples are of predominantly non-European ancestry, and Asian ancestry consisted of 8 % in total. In addition, 1000 Genomes Project(1KG) contains 2,504 individuals from 26 populations and has sequenced 698 samples in addition. These projects serve as a reference to impute missing variants to improve association power for Genome-Wide Association Study (GWAS) subsequently. We compared the imputation results using those reference panels. Korean Genome Project (Korea1K), including 1094 whole genomes are public datasets consisting of only Korean (East Asian) origin. On GRCh38, Korea1K variants consisting of 59,463,566 variants in total, 99.6% with MAF &amp;lt;1% rare variant, only 35.7% of those rare variants passed from GATK Best Practice VQSR filter. With Korea1K data, we have downsampled the result into the exonic level, imputed with reference panels, and seen the consequences for which reference panel shows the best performances. Using 1KG as a reference, we could identify novel rare variants only in 0.1 to 0.38 fold of filtered rare variant in 1KG phase3 and 1KG phase3 30X respectively. On the other hand, TOPMed imputation resulted in rare variants over 1.65 fold increase. With well-imputed variants R2 over 0.8, all three reference database showed poor conservation which only 0.009 % of rare variant are rescued. The reference panel we commonly use are large but required to have more diversity in a Asian rare variant perspective. Despite increase of the Asian fraction in the public genomic database, our result suggests that the number of reference Asian samples are still low to perform association study. In conclusion, our finding highlights both the utility and limitation of the imputation reference panel for Asian ancestry. Novel variants filled by imputation are promising for adding power to various association studies. Citation Format: GangPyo Ryu, Youngil Koh, Sung-soo Yoon. Method to increase performance of genome-wide association study using imputation for Asian ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6587.
Abstract 432: Mechanisms of acquired resistance to ARV-471, a novel PROTAC® estrogen receptor degrader
Authors: Jessica Teh, Shannon Bessonett, Wendy Wu, Christopher Kuhlberg, Alissa Wynne, Sean Landrette, Monica Andreoli, Elizabeth Bortolon, Jennifer Pizzano, Richard Gedrich, Ian Taylor
Journal: Cancer Research (2023)

Abstract ARV-471 is an orally bioavailable cereblon (CRBN)-based PROteolysis-TArgeting Chimera (PROTAC®) small molecule that demonstrates superior ER degradation and anti-tumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER-positive breast cancer patients. Innate and acquired drug resistance limits the response to and durability of many cancer therapies. To identify potential mechanisms of resistance to ARV-471, we generated ARV-471-resistant MCF7 cell lines which were then characterized using DNA, RNA and functional proteomic profiling. Acquired resistance to ARV-471 was associated with downregulation of ER protein expression and signaling and upregulation of HER family (EGFR, HER2, HER3) and MAPK/AKT signaling. NRAS copy number gain was also observed, which was accompanied by increased NRAS expression. Although EGFR, HER2 and HER3 expression and activation were upregulated, no corresponding genomic alterations were observed in resistant cells. Importantly, we show that NRAS and EGFR overexpression in MCF7 cells conferred resistance to ARV-471 in vitro. Furthermore, ARV-471-resistant cells with HER pathway upregulation were sensitive to EGFR and pan-HER inhibitors. Unlike recent reports indicating the association of E3 ligase alterations with PROTAC resistance, CRBN mutations/loss were not detected, nor were ESR1 mutations. CRBN knockout in ER+ breast cancer cells did not confer resistance to ARV-471, consistent with ARV-471 possessing ER antagonist activity independent of its degrader activity. Together, these data suggest that acquired resistance to ARV-471 may be associated with alterations within Receptor Tyrosine Kinase/MAPK signaling pathways rather than ER signaling or E3 ligase machinery. Citation Format: Jessica Teh, Shannon Bessonett, Wendy Wu, Christopher Kuhlberg, Alissa Wynne, Sean Landrette, Monica Andreoli, Elizabeth Bortolon, Jennifer Pizzano, Richard Gedrich, Ian Taylor. Mechanisms of acquired resistance to ARV-471, a novel PROTAC® estrogen receptor degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 432.
Abstract 4283: scMSI: Accurately detect the sub-clonal micro-satellite instability by an integrative Bayesian model
Authors: Yuqian Liu, Yan Chen, Huanwen Wu, Xuanping Zhang, Xin Lai, Xin Yi, Zhiyong Liang, Jiayin Wang
Journal: Cancer Research (2023)

Abstract Microsatellite instability (MSI) is an important genomic biomarker for cancer diagnosis and treatment. For some cancers with high-degree of heterogeneity, e.g. endometrial cancer, the existing approaches always fail to identify the micro-satellite instability on one or multiple sub-clones, which would deprive the chance for patients to benefit from treatments. However, it is a computational challenge to estimate the sub-clonal MSI because multiple sub-clones may share the genomic status. Herein, in this paper, we propose an accurate and efficient algorithm, named scMSI, to estimate the sub-clonal microsatellite status. scMSI adopts an alternating iterative model to de-convolute the length distribution, which is a mixture of sub-clones. During the deconvolution, an optimized division of each sub-clone is achieved by a heuristic algorithm, which is bounded to the clonal proportions best consistent with the known clonal structure. To evaluate the performance, we conducted a series of experiments on simulation datasets. The results supported that scMSI solved the detection problem of MSI on sub-clones. It outperforms the existing approaches on multiple metrics. In addition, we collected a cohort of 16 endometrial cancer patients, who have positive responses on the treatment but with negative MSI status. We sequenced these patients. scMSI reported MSI on sub-clones according the sequencing data, which are further validated by the conclusions on immunohistochemistry. Thus, scMSI could provide a powerful tool for MSI analysis. Citation Format: Yuqian Liu, Yan Chen, Huanwen Wu, Xuanping Zhang, Xin Lai, Xin Yi, Zhiyong Liang, Jiayin Wang. scMSI: Accurately detect the sub-clonal micro-satellite instability by an integrative Bayesian model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4283.
Abstract SY30-02: Oncosomes in the early stages of breast cancer
Authors: Peter Kuhn
Journal: Cancer Research (2023)

Abstract Comprehensive analysis of cellular, acellular and plasma components of the Liquid Biopsy provides the opportunity to investigate cancer evolution and the interactions with the immune system at the systemic level in the individual patient. This presentation will discuss early findings supporting the relevance of oncosomes, large extracellular vesicles, in early-stage breast cancer and its potential utility in early detection and cell-level staging of the disease when combined with the cellular profiles. Breast cancer (BC) affects 1 in every 8 women in the United States and is currently the most prevalent cancer worldwide. Precise staging at diagnosis and prognosis are essential components for the clinical management of BC patients. We set out to evaluate the feasibility of a next generation liquid biopsy platform to stratify late-stage BC, early-stage BC, and age- and gender matched controls using peripheral blood samples. Utilizing 5 biomarkers, we can identify rare circulating events with epithelial, mesenchymal, endothelial and hematological origin. We detected a higher level of CTCs in late-stage patients, compared to the early-stage and normal donors. We observed more tumor-associated oncosomes in the early-stage, compared to late-stage and the normal donor groups. Overall, we were able to detect reproducible patterns in the enumeration of rare cells and oncosomes of cancer vs. normal donors with an AUC of 99%. An initial concept for cell-level staging with the liquid biopsy was applied to early-stage vs. late-stage BC samples and reached an AUC of 91% allowing for robust stratification. Citation Format: Peter Kuhn. Oncosomes in the early stages of breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY30-02.
Abstract 1372: NUDT16L1 promotes colon cancer progression via inhibition of ferroptosis
Authors: Yi-Syuan Lin, Ya-Chuan Tsai, Chia-Jung Li, Tzu-Tang Wei, Ya-Na Wu, Shang-Rung Wu, Shin-Chin Lin, Shaw-Jenq Tsai, Shih-Chieh Lin
Journal: Cancer Research (2023)

Abstract Ferroptosis is an iron-dependent oxidative cell death with accumulation of lipid peroxidation and abnormal morphology of mitochondria. Although previous studies have shown that ferroptosis inducers have therapeutic potentials in several treatment-naive and drug-resistant cancer types, lacking systematic analysis of the ferroptosis sensitivity in different cancer types makes it difficult to know which cancer type is suitable for clinical usage and critical regulator determining the ferroptosis sensitivity during cancer progression is still not clear. In this study, colon cancer was identified as one of the ferroptosis-insensitive cancer types by dry and wet bench analyses. Importantly, our large-scale analysis also showed that NUDT16L1 was a novel ferroptosis repressor and overexpressed in colon cancer clinical specimens. Similar findings are also observed in the chemical-induced and genetic mouse models of colon cancer. Furthermore, NUDT16L1 loss-of-function and gain-of-function cell models and its conditional knock-in and knock-out mouse models are used to prove its crucial role in the development of colon cancer. In addition, loss of NUDT16L1 induced several key ferroptosis characteristics and impairment of mitochondrial functions while its restoration attenuated those phenomena in colon cancer cells. Mechanistically, our RNA-Seq and RIP-Seq analyses shown that NUDT16L1 directly interacted and positively regulated several crucial negative regulators of ferroptosis. More interestingly, loss of NUDT16L1 not only restores the sensitivity of ferroptosis inducer but also impairs the function of mitochondria. Finally, a specific NUDT16L1 inhibitor was shown to not only repress colon cancer growth in vitro and in vivo but also induce the ferroptosis in colon cancer. In conclusion, this is the first study to demonstrate that overexpression of NUDT16L1 promotes colon cancer progression by inhibition of ferroptosis and maintenance proper function of mitochondria. Furthermore, specific NUDT16L1 inhibitor might be a promising therapeutic strategy for colon cancer patient in the future. Citation Format: Yi-Syuan Lin, Ya-Chuan Tsai, Chia-Jung Li, Tzu-Tang Wei, Ya-Na Wu, Shang-Rung Wu, Shin-Chin Lin, Shaw-Jenq Tsai, Shih-Chieh Lin. NUDT16L1 promotes colon cancer progression via inhibition of ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1372.
Abstract 6128: Deubiquitinating enzyme Inhibitor PR-619 inducesendoplasmic reticulum stress-related apoptosisin human chondrosarcoma
Authors: Kuan-Lin Kuo, Chen-Hsun Hsu, Shih-Ming Liao, Kuo-Yuan Huang
Journal: Cancer Research (2023)

Abstract It is reported that PR-619 is a deubiquitination enzyme inhibitor that can exert anti-tumor effects on a variety of malignancies. We conducted this study to explore the antitumor effects of PR-619 on chondrosarcoma in vitro and in vivo by using two different classes of human chondrosarcoma cell lines SW-11353 and JJ012. To determine these effects, we measured cell viability (MTT), apoptosis (detection of Annexin V-FITC labeling using flow cytometry) and western blot to evaluate molecules associated with apoptosis and cell stress. In addition, we used a nude mouse xenograft mouse model to determine the effect of PR-619 on tumor growth. As our data revealed, in addition to inducing BAD and activating Capase-7, Caspase-8, and PARP, PR-619 also has a dose-effect that induces cytotoxicity, proliferation restriction, and apoptosis in these human chondrosarcoma cells. PR-619 has also been found to activate endoplasmic reticulum pressure-related molecules (caspase-4 and CHOP) and other stress responses (activation of JNK and c-Jun). We conclusively demonstrated the ability of PR-619 to inhibit tumor growth while achieving minimal general toxicity in a developed xenograft mouse model of chondrosarcoma. Therefore, we conclude that PR-619 exacts an antitumor effect in conjunction with cellular and endoplasmic reticulum pressure in human chondrosarcoma. These findings suggest that PR-619 may provide a novel therapeutic strategy for chondrosarcoma. Citation Format: Kuan-Lin Kuo, Chen-Hsun Hsu, Shih-Ming Liao, Kuo-Yuan Huang. Deubiquitinating enzyme Inhibitor PR-619 inducesendoplasmic reticulum stress-related apoptosisin human chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6128.
Abstract 2945: Depleting hCCR8 mAb Therapy #2: Selection of candidates for the development of innovative depleting anti CCR8 therapeutic antibodies to control the immunosuppressive tumor microenvironment
Authors: Alice Gentil Dit Maurin, Iseulys Richert, Maria Dolores Garcia Fernandez, Aurélie Janvier, Solene Rose, Megane Jeannelle, Dounia Chraa, Camille Dietsch, Pauline Urquia, Quentin Ruet, Malaury Schappler, Luc Baron, Safia Ayachi, Orphée Blanchard, Christel Franchet, Alexandre Fontayne, Claudine Vermot-Desroches, Stephan Schann, Nathalie Lenne
Journal: Cancer Research (2023)

Abstract Tumor-infiltrating Tregs (TITR) constitute a sub-family of immuno-suppressive cells abundantly found in multiple solid cancers. They play a critical role in tumor progression and their specific depletion has been recently propose as a novel therapeutic strategy to fight cancers. Based on the transcriptional analysis of tumor infiltrating immune cells, the G-protein coupled receptor CCR8 was found to be expressed on murine and human TITR, but not on proinflammatory effector T cells. The CCR8 receptor therefore represents a unique TITR target for the development of novel depletive antibody-based therapeutics. At Domain Therapeutics, a diverse library of several dozens of mouse mAbs directed against the hCCR8 was discovered and characterized, providing a unique source for the development of a best-in-class and well differentiated anti-hCCR8 depleting antibody for the treatment of cancers.Special attention was paid on two important characteristics for the selection of our depleting mAb candidates: (1) their ability to detect all CCR8 positive immunosuppressive cells and (2) the combination of different killing modes of action (ADCC, ADCP, CDC) to trigger an optimal depletion.Our selected mAb candidates were nominated based on their capacity to bind to immunosuppressive cells present in different tumor tissues and optimal depleting activity. The impact of our mAbs on tumor growth and on the immune tumor microenvironment (TME) were also studied in mouse hCCR8-KI mice. Finally, following a comprehensive in vitro benchmarking mAb analysis, we identified key differentiating points versus competitor’s mAbs. Nominated candidates wil be ready to enter cell line generation efforts in early 2023. Citation Format: Alice Gentil Dit Maurin, Iseulys Richert, Maria Dolores Garcia Fernandez, Aurélie Janvier, Solene Rose, Megane Jeannelle, Dounia Chraa, Camille Dietsch, Pauline Urquia, Quentin Ruet, Malaury Schappler, Luc Baron, Safia Ayachi, Orphée Blanchard, Christel Franchet, Alexandre Fontayne, Claudine Vermot-Desroches, Stephan Schann, Nathalie Lenne. Depleting hCCR8 mAb Therapy #2: Selection of candidates for the development of innovative depleting anti CCR8 therapeutic antibodies to control the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2945.
Abstract 5998: Global DNA methylation analysis of cancer-associated fibroblasts reveals extensive epigenetic rewiring linked with RUNX1 upregulation in breast cancer stroma
Authors: Coral Halperin, Joschka Hey, Dieter Weichenhan, Yaniv Stein, Shimrit Mayer, Pavlo Lustik, Christoph Plass, Ruth Scherz-Shouval
Journal: Cancer Research (2023)

Abstract Cancer cells recruit and rewire normal cells in their microenvironment to support and protect them by creating a pro-tumorigenic tumor microenvironment (TME). We lack an overarching view of how, despite being genomically stable, stromal cells in the tumor microenvironment are heterogeneously reprogrammed across time and space to promote the evolution of aggressive disease. Recent work by us and others has shown that fibroblasts in the tumor microenvironment are transcriptionally rewired to become protumorigenic cancer associated fibroblasts (CAFs). Transcriptional regulation plays a major role in this reprogramming, but the extent to which epigenetic modifications of DNA also contribute to the rewiring of CAF transcription is not clear. Here we address this question by dissecting the epigenetic landscape of breast CAFs. We applied a sensitive method of whole genome bisulfide sequencing on a model of triple-negative breast cancer in mice to evaluate the methylome profile of CAFs compared to normal mammary fibroblasts (NMFs). we found that fibroblasts undergo massive DNA methylation changes as they transition into CAFs in mice. These changes inversely correlated with transcriptional changes between CAFs and NMFs. We characterized potential regulators of this process, and tested their expression in CAFs in human breast cancer patients, to confirm relevance of our findings to human disease. Our findings suggest that epigenetic alterations contribute to the transcriptional rewiring of fibroblasts to CAFs. This work presents a comprehensive map of DNA-methylation in CAFs, and reveals a previously unknown facet of the dynamic plasticity of the stroma. Citation Format: Coral Halperin, Joschka Hey, Dieter Weichenhan, Yaniv Stein, Shimrit Mayer, Pavlo Lustik, Christoph Plass, Ruth Scherz-Shouval. Global DNA methylation analysis of cancer-associated fibroblasts reveals extensive epigenetic rewiring linked with RUNX1 upregulation in breast cancer stroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5998.
Abstract 5956: Tumor-infiltrating neutrophil progenitors impair homologous DNA repair and promote sensitivity to PARP-inhibition
Authors: Arianna Calcinotto
Journal: Cancer Research (2023)

Abstract Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identified a novel subset of tumor-infiltrating neutrophils, defined as tumor-associated neutrophil progenitors (NePs). These NePs are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity. Mechanistically, succinate secreted by tumor-associated NePs inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability, resulting in tumor progression and resistance to endocrine therapies. Selective inhibition of these pathways induces increased tumor cell kill in vitro and in vivo. Intra-tumor NePs score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumorigenic effect of these neutrophils and reverses endocrine resistance. Citation Format: Arianna Calcinotto. Tumor-infiltrating neutrophil progenitors impair homologous DNA repair and promote sensitivity to PARP-inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5956.